One of the curious things about Neuroendocrine Cancer (NET Cancer) is that it can exhibit one or more vague symptoms collectively known as a ‘syndrome’. Syndrome is an apt word to describe these complications as the most general meaning in medical terms is “
Most people think of Carcinoid Syndrome when they discuss NET Cancer but there are in actual fact, several associated syndromes depending on the location and type of NET Cancer. Not everyone will have a ‘syndrome’ in addition to their tumours. Take the most common form of NET Cancer as an example – statistics vary from source to source but it is estimated that around a 30-45% of all ‘midgut’ patients will present with metastatic disease and around a third of those (∼10-15% of all midgut) will exhibit Carcinoid Syndrome indicating their tumours are functional (secreting excess hormones, particularly serotonin). It follows that Carcinoid Syndrome itself is not that common and it could be the same with other types of NET Cancer (even though it can appear more prevalent on forums). In fact a large proportion of Pancreatic NETs are non-functional at diagnosis.
These tumours and associated syndromes are treatable for most but the difficult part can be arriving at a diagnosis. Moreover, without a syndrome, some of these tumours can be silently growing and as they grow slowly, the ‘silence’ can go on for some years. Even with a syndrome, the root cause can remain disguised as the symptoms are similar to many day-to-day illnesses, again the reason for the title of this blog. Curiously, the lack of a syndrome can sometimes lead to an even later presentation and the consequences that arise (i.e. no signs to aid a diagnosis). There can be the odd exception but in general terms, NETs are either functional (with a syndrome) or non-functional (no syndrome).
The ISI Book on Neuroendocrine Tumors 2016 (Woltering et al) confirms there are a number of syndromes associated directly and indirectly with NET Cancer. For example Carcinoid, Gastrinoma, Insulinoma, Somatostatinoma, Glucagonoma, and VIPoma are described as individual syndromes according to their secretory hormones and peptides. The referenced publication expands on this list to aid diagnoses by including common presentations, associated tumour types and locations and the offending secreting hormones. You can see why NET Cancer is a diagnostic challenge!
Major NET Syndromes – (information mainly taken from the ISI Book on NETs with a cross reference from ENETS Guidelines):
Carcinoid – a syndrome connected with conventional carcinoid locations (small intestine, lung, stomach, appendix etc). Type 2 Gastric NET can also be associated with Zollinger-Ellinson Syndrome (ZES) see below.
(there’s also a very rare instance of pancreatic tumours (PNETs) producing carcinoid syndrome effects – according to ENETs less than 1% of all ‘carcinoid tumours’)
Insulin – Insulinoma (Whipple’s Triad) – Whipple’s Triad is the classic description of insulinoma which includes symptoms of hypoglycemia with a low blood glucose concentration relieved by the ingestion of glucose. These tumours can be located anywhere within the pancreas in the cells that make insulin. Insulin is a hormone that controls the amount of glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. Some of these tumours will be associated with MEN1.
Gastrin – Gastrinoma A tumour that forms in cells that make gastrin. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. When increased stomach acid, stomach ulcers and diarrhea are caused by a tumour that makes gastrin, it is called Zollinger-Ellinson Syndrome (see also below). Gastrinoma usually forms in the head of the pancreas. Some of these tumours may be associated with MEN1 syndrome.
Glucagon – Glucagonoma. A tumour that forms in cells that make make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas. Some of these tumours may be associated with MEN1 syndrome. See also Sweet’s Syndrome below.
Pancreatic Polypeptide (PP) – PPoma. A complicated one and not too much information (even in the ISI book). However, it’s the third most common type of islet cell tumour (i.e. pNET). The function of pancreatic polypeptide is not completely understood. Patients present with weight loss, jaundice, and abdominal pain. The diagnosis is confirmed by pancreatic polypeptide levels > 300 pg/ml. Some of these tumours may be associated with MEN1 syndrome.
Vasoactive Intestinal Peptide (VIP) – VIPoma – Sometimes the syndrome is referred as WDHA – Watery Diarrhea, Hypokalemia (potassium deficiency), and Achlorhydria (absence of hydrochloric acid in gastric secretions). Also known as Werner-Morrison Syndrome or Pancreatic Cholera.
Somatostatin – Somatostatinoma is a very rare NET, with an incidence of one in 40 million persons. These tumours arise from the delta cells in the pancreas, although these cells can also be present in duodenal tissue where around 40% of these tumours occur. Somatostatin is a naturally occurring peptide that inhibits the function of almost all gut hormones (author’s note – this should give you an appreciation of how somatostatin analogues tackle associated syndromes but gives you certain side effects as a result!)
Hedinger Syndrome – the technical term for Carcinoid Heart Disease.
MEN1 – Mainly involved the 3 Ps, Pituitary, Pancreas and Parathyroid. The pituitary tumours are primarily Prolactinomas, the pancreatic tumours are mainly PPomas, Gastrinomas and Insulinoma. Many also have association with Zollinger-Ellinson syndrome (ZES). Read more here. Previously known as Wermer Syndrome.
Von Hippel-Lindau (VHL) – not an exclusively NET syndrome. VHL is a rare disorder caused by a faulty gene. It is named after the two doctors who first described the disease, and affects about one in 35,000 people. Tumours develop in one or more parts of the body. Many of these tumours involve the abnormal growth of blood vessels in parts of the body which are particularly rich in blood vessels. Areas most frequently affected are the eyes, the back of the brain (cerebellum), the spinal cord, the kidneys, the adrenal glands and the pancreas. People are affected differently, even within the same family. The only VHL tumour which tends to run in families affects the adrenal glands (Pheochromocytoma).
Different VHL features tend to develop at different ages. The eye angiomas often develop in childhood. Others, including tumours found in the cerebellum, spinal cord or adrenal glands (Haemangioblastomas and Pheochromocytomas) can develop from late childhood onwards. The kidney tumours are usually the last things that develop, from the mid-twenties onwards. Most VHL related tumours are benign,
Zollinger-Ellinson Syndrome (ZES). This is a condition in which one or more tumours form in the pancreas, the upper part of the duodenum or the stomach. These tumours secrete large amounts of the hormone gastrin, which causes your stomach to produce too much acid. The excess acid can lead to peptic ulcers, in addition to diarrhea and other symptoms. Associated with Gastrinoma (pNET) and Type 2 Gastric NETs.
Cushing’s – also known as hypercortisolism. A collection of symptoms caused by very high levels of a hormone called cortisol in the body. Associated with AdrenoCorticoTropic Hormone (ACTH). In Cushing’s disease, oversecretion of pituitary ACTH induces bilateral adrenal hyperplasia. This results in excess production of cortisol, adrenal androgens, and 11-deoxycorticosterone. Cushing’s disease, a subset of Cushing’s syndrome, is due to a pituitary corticotroph adenoma and results in a partial resistance to the suppression of ACTH by cortisol so that secretion is unrestrained. In contrast, causes of Cushing’s syndrome may include the following:
• Adrenal adenoma or carcinoma arise spontaneously. ACTH levels are undetectable.
• Non-pituitary (ectopic) tumours produce ACTH. They most frequently originate in the thorax and are highly aggressive small cell carcinomas of the lung or slow- growing bronchial or thymic carcinoid tumours. Some produce corticotropin- releasing hormone (CRH) instead, which stimulates pituitary ACTH secretion and can therefore mimic a pituitary tumour.
• Other causes include carcinoid tumours of the gastric, pancreatic, and intestinal organs; Pheochromocytomas, and MCT.
The hallmark of Cushing’s syndrome is that ACTH levels are partially resistant to suppression with dexamethasone, even at very high doses. Some MEN patients with pituitary tumours may have Cushing’s Syndrome.
ACTHoma is essentially the pancreatic tumour version related to Cushing’s Syndrome.
Sweet’s – Dermatitis/rash associated with Glucagonomas. Not to be confused with Pellagra.
There are many other less known syndromes that appear to be directly or indirectly connected with Neuroendocrine Tumours and I may update this blog if I discover they are more prevalent than I think.
As for my own experience of syndromes, I did once show symptoms of the most common NET syndrome (currently known as Carcinoid syndrome) where the key symptoms are flushing, diarrhea and wheezing. You can see why those symptoms are frequently and easily confused with other conditions. If you have a similar diagnosis, y
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